Adverse drug reaction (ADR, or adverse drug effect) is a broad term referring to unwanted, uncomfortable, or dangerous effects that drugs (including medications ) may have.
Adverse drug reactions can be considered a form of toxicity; however, toxicity is most commonly applied to effects of overingestion (accidental or intentional) or to elevated blood levels or enhanced drug effects that occur during appropriate use (eg, when drug metabolism is temporarily inhibited by a disorder or another drug). For information on toxicity of specific drugs, including medications, see the table Symptoms and Treatment of Specific Poisons. Side effect is an imprecise term often used to refer to the unintended effects of a medication that occur within the therapeutic range.
Because all drugs have the potential for adverse drug reactions, conducting a risk-benefit analysis (the likelihood of benefit vs risk of ADRs) is necessary whenever a medication is prescribed.
The National Electronic Injury Surveillance System–Cooperative Adverse Drug Event Surveillance Project (NEISS–CADES) estimated that there were 6 emergency department (ED) visits for medication harms per 1000 persons per year in the period from 2017 to 2019 based on a sample of almost 100,000 cases (1). About 39% of these visits resulted in hospitalization (1). In previous estimates in the United States, 3 to 7% of all hospitalizations were due to adverse drug reactions. ADRs occurred during 10 to 20% of hospitalizations; about 10 to 20% of those ADRs were severe. These statistics do not include the number of ADRs that occur in other ambulatory and nursing home patients. Although the exact number of ADRs is not certain, ADRs represent a significant public health problem that is, for the most part, preventable (2, 3).
Incidence and severity of adverse drug reactions vary by patient characteristics (eg, age, sex, ethnicity, coexisting disorders, genetic or geographic factors) and by drug factors (eg, type of drug, administration route, treatment duration, dosage, bioavailability). Incidence is higher with advanced age and polypharmacy. According to the National Electronic Injury Surveillance system, in older adults, therapeutic use of anticoagulants and diabetes medications led to ED visits most often. Nontherapeutic use of sedative and hypnotic drugs such as benzodiazepines and analgesics also contributed to drug-related harm. For children under 5 years of age, antibiotic use was a frequent cause of ED visits due to medication-related harm (1).
ADRs are more severe among older patients (see Drug-Related Problems in Older Adults), although age per se may not be the primary cause. Fatal adverse drug reactions occur mainly in patients older than 75 years of age, according to the World Health Organization's pharmacovigilance database (4).The contribution of prescription errors and poor adherence to the incidence of ADRs is unclear.
Pearls & Pitfalls
|
General references
1. Budnitz DS, Shehab N, Lovegrove MC, et al: US emergency department visits attributed to medication harms, 2017-2019. JAMA 326 (13):1-11, 2021. doi: 10.1001/jama.2021.13844
2. Weiss AJ, Freeman WJ, Heslin KC, et al: Adverse drug events in U.S. hospitals, 2010 versus 2014. Agency for Healthcare Research and Quality. Statistical Brief #234. January 2018. Accessed February 2, 2023.
3. PSNet (Patient Safety Network), Agency for Healthcare Research and Quality: Medication errors and adverse drug events. Accessed February 2, 2023.
4. Montastruc J-L, Lafaurie M, de Canecaude C, et al: Fatal adverse drug reactions: A worldwide perspective in the World Health Organization pharmacovigilance database. Br J Clin Pharmacol 87(11):4334-4340, 2021. doi: 10.1111/bcp.14851
Etiology of Adverse Drug Reactions
Most adverse drug reactions are dose-related; others are allergic or idiosyncratic. Dose-related ADRs are usually predictable; ADRs unrelated to dose are usually unpredictable.
Dose-related ADRs are particularly a concern when medications have a narrow therapeutic index (eg, hemorrhage with oral anticoagulants). ADRs may result from decreased drug clearance in patients with impaired renal or hepatic function or from drug-drug interactions.
Allergic ADRs are not dose-related and require prior exposure. Allergies develop when a drug acts as an antigen or allergen. After a patient is sensitized, subsequent exposure to the drug produces one of several different types of allergic reaction. Clinical history and appropriate skin tests can sometimes help predict allergic ADRs.
Idiosyncratic ADRs are unexpected ADRs that are not dose-related or allergic. They occur in a small percentage of patients given a drug. Idiosyncrasy is an imprecise term that has been defined as a genetically determined abnormal response to a drug, but not all idiosyncratic reactions have a pharmacogenetic cause. The term may become obsolete as specific mechanisms of ADRs become known.
Symptoms and Signs of Adverse Drug Reactions
Adverse drug reactions are usually classified as mild, moderate, severe, or lethal (see table Classification of Adverse Drug Reactions [ADRs]). Severe or lethal ADRs may be specifically mentioned in black box warnings in the physician prescribing information provided by the manufacturer.
Symptoms and signs may manifest soon after the first dose or only after chronic use. They may obviously result from drug or medication use or be too subtle to identify as related to that drug or medication. In older adults, subtle ADRs can cause functional deterioration, changes in mental status, failure to thrive, loss of appetite, confusion, and depression.
Allergic ADRs typically occur soon after a drug is taken but generally do not occur after the first dose; typically, they occur when the drug is given after an initial exposure. Symptoms can include itching, rash, fixed-drug eruption, upper or lower airway edema with difficulty breathing, and/or hypotension.
Idiosyncratic ADRs can produce almost any symptom or sign and usually cannot be predicted.
Diagnosis of Adverse Drug Reactions
Consideration of rechallenge
Reporting of suspected ADRs to MedWatch
Symptoms that occur soon after a drug or medication is taken are often easily connected with use of that drug or medication. However, diagnosing symptoms due to chronic use of a drug or medication requires a significant level of suspicion and is often complicated. Stopping a medication is sometimes necessary but is difficult if the medication is essential and does not have an acceptable substitute. When proof of the relationship between medication and symptoms is important, rechallenge should be considered, except in the case of serious allergic reactions.
Physicians should report most suspected adverse drug reactions to MedWatch (the Food and Drug Administration's [FDA’s] ADR monitoring program), which is an early alert system. Only through such reporting can unexpected ADRs be identified and investigated. MedWatch also monitors changes in the nature and frequency of ADRs. Online reporting of ADRs is encouraged. Forms for and information about reporting ADRs are available in the Physicians’ Desk Reference and the FDA News Daily Drug Bulletin, as well as at the FDA Adverse Event Reporting System (FAERS; MedWatch: The FDA Safety Information and Adverse Event Reporting Program ). Nurses, pharmacists, and other health care practitioners should also report ADRs via FAERS, which also functions as a search tool that improves access to data about adverse drug reactions (1).
The incidence of severe or fatal adverse drug reactions is very low (typically < 1 in 1000) and may not be apparent during clinical trials, which are typically not powered to detect low-incidence ADRs. Thus, these ADRs may not be detected until after a medication is released to the general public and is in widespread use. Clinicians should not assume that because a drug is on the market that all ADRs are known. Postmarketing surveillance is extremely important for tracking low-incidence ADRs.
Diagnosis reference
1. FDA Adverse Event Reporting System (FAERS): Questions and Answers on FDA's Adverse Event Reporting System (FAERS). Accessed February 2, 2023.
Treatment of Adverse Drug Reactions
Modification of dosage
Discontinuation of drug or medication if necessary
Switching to a different medication
Prevention of Adverse Drug Reactions
Prevention of adverse drug reactions (ADRs) requires familiarity with the medication and potential reactions to it. Computer-based analysis should be used to check for potential drug interactions; analysis should be repeated whenever medications are changed or added. Medications and initial dosage must be carefully selected for older adults (1). (See Reasons for Drug-Related Problems.) If patients develop nonspecific symptoms, ADRs should always be considered before beginning symptomatic treatment.
Various genes have been identified as having an association with ADRs. For example, multiple liver enzymes that affect liver metabolism of cytochrome P450 have been characterized, and many are affected by single nucleotide polymorphisms, leading to clinically meaningful effects on a wide range of commonly prescribed medications. Therefore, pharmacogenomics may help to predict, reduce, and minimize ADRs (2, 3, 45]).
Prevention references
1. 2019 American Geriatrics Society Beers Criteria® Update Expert Panel: American Geriatrics Society 2019 updated AGS Beers Criteria® for potentially inappropriate dedication use in older adults. J Am Geriatr Soc 2019, 67(4):674-694. doi: 10.1111/jgs.15767
2. Zhou Z-W, Chen X-W, Sneed KB, et al: Clinical association between pharmacogenomics and adverse drug reactions. Drugs 75:589-631, 2015. doi: 10.1007/s40265-015-0375-0
3. Gerogianni K, Tsezou A, Dimas K: Drug-induced skin adverse reactions: The role of pharmacogenomics in their prevention. Mol Diagn Ther 22(3): 297-314, 2018. doi: 10.1007/s40291-018-0330-3
4. Micaglio E, Locati ET, Monasky MM, et al. Role of pharmacogenetics in adverse drug reactions: An update towards personalized medicine. Front Pharmacol 12:651720, 2021 https://doi.org/10.3389/fphar.2021.651720
5. Bardolia C, Matos A, Michaud V, et al: Utilizing pharmacogenomics to educe adverse drug events. Am J Biomed Sci & Res 11(3). doi: 10.34297/AJBSR.2020.11.00163
